Treatment options for adult patients with leukemia remain sub-optimal, and therefore new rationally designed therapies are needed. Two epigenetic alterations are currently the focus of intense investigation: DNA methylation of promoter CpG islands, and changes in the histone code associated with distinct levels of chromatin compaction and gene expression. These are of interest because: 1) they are observed at high frequency in patients with leukemia; 2) both have a role in gene expression and are intimately associated; and 3) can be modulated using hypomethylating agents and histone deacetylase inhibitors (HDACI) with preclinical and clinical activity. Results of a phase I study of low-dose 5-aza-2'-deoxycytidine (decitabine), a hypomethylating agent, performed at our institution, have shown that decitabine has significant activity at doses of 15 mg/m2 daily X 10 days. Valproic acid is an oral anti-convulsant agent with potent HDACI activity at physiological doses, also with an excellent safety profile. Based on this, we propose the hypothesis that the combination of decitabine and valproic acid will be well tolerated and will have significant antileukemia activity. To test this hypothesis, we propose the following aim: to conduct a phase I/II study of low-dose decitabine with escalating doses of valproic acid. The study will be monitored for toxicity, clinical response, and changes in histone acetylation, DNA methylation and gene expression. This study will have important implications, as it will provide fundamental knowledge regarding the clinical and molecular implications in vivo of the combination of a DNA hypomethylating agent and a HDACI. Decitabine will be generously provided by SuperGen (r). Valproic acid is an FDA approved anti-convulsant.